Patients with insulin dependent diabetes mellitus (IDDM; Type 1 diabetes) display higher bone loss and increased risk for osteoporosis and related bone fractures. However, the mechanisms that underlie bone loss in IDDM are still not fully understood. It is well established that bone mass is maintained by bone remodeling, a process that involves formation of new bone by osteoblasts and osteocytes and resorption of existing bone by osteoclasts. Bone remodeling is regulated by mechanical stimuli imposed continuously to the skeleton by physical activity, and proper response of osteocytes/osteoblasts to mechanical loading is thus essential for maintenance of bone function and skeletal integrity. The main goal of this R01 application is to test the novel hypothesis that altered expression of components of bone mechanosensory and transduction systems is a central mechanism leading to bone cell dysfunction and higher bone loss in IDDM. For this we will use comprehensive in vitro studies with bone cell lines that will be uniquely combined with in vivo bone physiology and in situ bone tissue analysis on the Type 1 diabetic Akita mouse model. The proposed in vitro studies will provide mechanistic insights into effects of high glucose on bone cell detection and response to mechanical stimuli. The in vivo and ultimate in situ studies with control age- matched and Akita mice treated with or without insulin will determine the impact of diabetes and associated high glucose on bone formation in response to mechanical loading, and evaluate the contribution of altered bone mechanosignaling to the higher bone loss in diabetes. These studies will be directed by a new investigator who has a background in biomedical engineering and has begun a first faculty appointment in a Department of Orthopaedic Surgery. Studies will combine the broad expertise of junior and senior researchers in the areas of biomedical engineering, pharmacology, physiology and molecular biology, and state-of-the-art biochemical, live cell imaging, histomorphometric studies and non-invasive in vivo whole animal bone imaging. The proposed studies are not only expected to advance understanding of mechanisms underlying diabetic osteopenia, highlighting the deleterious effects of high glucose on bone mechanosensory/transduction systems, but will also bring awareness to the importance of an early and tight glycemic control to prevent and reverse bone loss in diabetes.